Process for the manufacture of n1-acylated aminoarylsulfonamides



Patented Jan. 12, 1954 UNITED STATES PATENT o F F-IC E raoopss ,FOR THE MANUFACTURE 'oF n ncrm'mo AMINOARYLSULFONAMIDES Josef Matzke, Linz(Donau), Austria, assignor to Osterreichische Stickstofiwerke Aktiengesellv schaft, Linz(Donau) Austria, an Austrian joint stock company No Drawing. Application January 4, 1952, Serial No. 265;053

Claims priority, application Austria January 19, 1951 Which are acylatedat the N -position have, among others, proved in particular to be of excellent pharmacological efiect. These also have the val uable property of forming in water-easily soluble, almost neutral alkali salts eminently suitable for injection purposes.

In addition to medical purposes, compounds of this type are of interest also in the hold of plasticizers, as a dyestuff component, and as a starting material for disinfectants and insecticides, etc.

The preparation of amino sulphonamides 'acylated at the N -position is the subject of nu- 'merous publications and patents. The most obvious Way to mono-acylate the N -amino group formula of amino-aryl sulphonamides, when following the usual instructions, having failed by previous exbe carried out in two stages of manufacture.

Previously a mono-acylation at the il -nitrogen atom has been possible only in organic solvents in the presence of strong mineral acids (see U. S. Patent No. 2,454,104 of November 16, 1948, U. S. Schering (30.; and Swiss Patent No. 260,993, Class 1l6h, of November 1, 1949, Dr. A. Wander A. (3., Bern), and it is necessary to take strict care to exclude water. As a matter of course, heavy corrosion is to be expected with this method of working.

In acylating amino-aryl sulphonamides with a free amino group in an alkaline aqueous medium, by previous experience, an aoylation has been possible only at the N -position or at both the N and N -positions. In accordance with that meth-- od, it has not been possible to prepare in a single stage products that are preponderantly acylated at the N -pos'ition where the formation or diacyl compounds as intermediate products is to be avoided '(see, e. g., Norwegian Patent No. 63,30? (Schering), Example 8, and Chem. Bericht-e 83, 553 (1950) J .See also British Patent No. 642 013 of August'23, 1950,1'11 which also the indirect way, over diacyl products or the 'nitro compound, is described, which intermediate products must be performed subsequently into compoundsyzith afree amino group, by saponification o'r reduction; thus a multi-stage process appears also necessary here.

Surprisingly it has been found 'tliat in aminoaryl sulphonamides with a free ammogrcepeiso the desired N -acyl compound may [be obit ne'd in a single operation with-satisfactory yields'by a treatment of amino-aryl sulphonanii'desyjith acylating agents, if the reaction is 'conduc't'e dso that the reaction mixture remains alkalineduracid, butyric acid, efi-dimethylacrylic acid, herb zoic acid, maybe used as acylating agent's.

"Suitably the reaction proceeds with a moderate increase of temperature and in caseit will be completed within a short time.

The separation of the desired N -acyl product "from a moderate amount of 'unreac'ted'starting product may be eflected easily by precipitation with a pH changed step by step, in 'the'manner known.

It may be mentioned here that the amino aryl sulphonamides to be taken into consideration may consist, instead of sulphanilamide or the corresponding 0- and m-proclucts used-as starting material, as mentioned in the examples, of derivatives of the same that are substituted at the aryl nucleus with alkyl", halogen-', nitro acylamino groups, etc.

As compared with the previously known methods the new method of working provides the advantage of being carried out in a non-corroding medium and of the reaction being completed in a single-stage operation and within short time, whereas only that amount of acylating agent is used which is just required :for an acyl group to be introduced.

Example 1.-0.l mol=172 g. of sulphanilamide, 0.3 mol=l2 g. of caustic soda, and 20 c. c. of water are brought into solution by being heated (approximately 0.). At this temperature while the solution is being stirred 0.154 11:01:14.5 c. c. of acetic anhydride are added in drops, in the course of 15 minutes. After being stirred for further 15 minutes the solution is diluted with some water, to obtain in solution the sodium salts separating in the cold, and is adjusted to pH 8 with some hydrochloric acid. After separating unreacted sulphanilamide (6.9 g.) a further acidulation to pH 4 leads to the precipitation of 10.7 g. of crude N -acetyl compound,

which yields 9.6 g. of pure N -acetyl sulphanib.

amide after a single recrystallization from a small amount of water (melting point 180 to 181 0.).

Taking into account the starting material recovered the yield of pure N -acetyl sulphonamide is more than 70% of theory, and where the starting material recovered is not taken into account the yield is 45% of theory.

Example 2.-1 mol=172 g. of sulphanilamide, 1.125 mol=45 g. of caustic soda, and 200 c. c. of water are brought into solution (approximately 45 C.) and at this temperature, while the solution is being stirred, a solution of 1.925 mol=77 g. of caustic soda in 100 c. c. of water, on the one hand, and 1.44 mol=l36 c. c. of acetic anhydride, on the other hand, are separately though at the same time added thereto within 30 minutes.

After being stirred for further 15 minutes the solution is diluted with some water and is adjusted with concentrated hydrochloric acid to pH 8. After the separation of unreacted sulphanilamide (30.3 g.) a further acidulation to pH 4 leads to the precipitation of 130 g. (approximately 60% of theory) of crude N -acetyl compound, which after recrystallization from water yields 116 g. of pure N -acetyl sulphanilamide (54% yield); when the starting material recovered is taken into account this yield of pure N acetyl product (melting point 180 to 181 C.) is increased to 66%.

In the same manner, when starting from sulphanilamide, N -548-dimethy1acrylic sulphanilamide (M. P.-177-178 C.) may be obtained with 3.5-

dimethylacrylic acid anhydride, N -propionic sulphanilamide (M. P. 134-135 C.) with propionic anhydride, N -hutyric sulphanilamide (M. P. 125-126 C.) with butyric anhydride, and N -benzoic sulphanilamide (M. P. 181182 C.) with benzoic chloride.

I claim:

1. A process for making N -acylated 4amino aryl sulphonamides which have a free primary amino group attached directly to the aryl radical, comprising the steps of dissolving 4-aminoaryl sulphonamide in an alkaline medium, reacting said dissolved l-aminoaryl sulphonamide in a single stage with an anhydride of a monocarboxylic acid, while maintaining the pH of the reaction mixture between 9 and 14 during the entire reaction, and separating the reaction product therefrom.

2. The process as claimed in claim 1, wherein the pH of the reaction mixture is maintained between 11 and 12.

3. A process for making N -acylated 4-aminoaryl sulphonamides which have a free primary amino group attached directly to the aryl radical, comprising the steps of dissolving 4-aminoaryl sulphonamide in an alkaline medium, reacting said dissolved -aminoaryl sulphonamide in a single stage with an anhydride of a monocarboxylic acid selected from the group consisting of acetic acid, propionic acid, butyric acid, 3,5- dimethyl acrylic acid and benzoic acid, while maintaining the pH of the reaction mixture between 9 and 14 during the entire reaction, and separating the reaction product therefrom.

4. A process as claimed in claim 3, wherein the pH of the reaction mixture is maintained between 11 and 12.

5. A process as claimed in claim 3, wherein the said alkaline medium is a solution of sodium hydroxide in water.

6. A process as claimed in claim 5, wherein the pH of the reaction mixture is maintained between 11 and 12.

7. A process for making N -acylated 4-aminoaryl sulphonamides having a free primary amino group attached directly to the aryl radical, comprising the steps of dissolving -aminoaryl sulphonamide in a solution of sodium hydroxide in Water, reacting said dissolved 4aminoaryl sulphonamide with an anhydride of a monocarboxylic acid selected from the group consisting of acetic acid, propionic acid, butyric acid, 6,5-dimethyl arylic acid and benzoic acid, at elevated temperatures between 30 C. and 75 C., while maintaining the pH of the reaction mixture between 9 and 14 during the entire reaction, and separating the reaction product therefrom.

8. A process as claimed in claim '7, wherein the pH of the reaction'mixture is maintained between 11 and 12.

J OSEF MATZKE.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,411,495 Dohrn et a1 Nov. 19, 1946 FOREIGN PATENTS Number Country Date 556,425 Great Britain Oct. 5, 1943 558,225 Great Britain Dec. 28, 1943 595,235 Great Britain Nov. 28, 1947 604,259 Great Britain June 30, 1948 850,553 France Sept. 18, 1939 863,481 France Jan. 2, 1941 OTHER REFERENCES Dewing et a1.: J. Chem. Soc. (London), 1942, pp. 239-243. 

1. A PROCESS FOR MAKING N1-ACYLATED 4-AMINOARYL SULPHONAMIDES WHICH HAVE A FREE PRIMARY AMINO GROUP ATTACHED DIRECTLY TO THE ARYL RADICAL, COMPRISING THE STEPS OF DISSOLVING 4-AMINOARYL SULPHONAMIDE IN AN ALKALINE MEDIUM, REACTING SAID DISSOLVED 4-AMINOARYL SULPHONAMIDE IN A SINGLE STAGE WITH AN ANHYDRIDE OF A MONOCARBOXYLIC ACID, WHILE MAINTAINING THE PH OF THE REACTION MIXTURE BETWEEN 9 AND 14 DURING THE ENTIRE REACTION, AND SEPARATING THE REACTION PRODUCT THEREFROM. 